Huntington's disease (HD) is a well defined hereditary disorder characterized by neuronal degeneration and progressive disability. Only palliative therapies are available. Although the pathogenesis of DH has not been fully clarified, neuronal populations in striatum and other basal ganglia regions are particularly vulnerable to the consequences of gene expression. Accumulating evidence from studies of HD patients and laboratory animals suggests that neuronal degeneration is related to a toxic process mediated by altered sensitivity to glutamate. To date, no clinical studies have assessed whether long-term attenuation of glutamatergic neurotransmission might protect against neuronal degeneration and thereby forestall the relentless deterioration of HD patients. Based on the evidence that baclofen reduces presynaptic glutamate release and that the corticostriatal glutamatergic pathway is preserved in HD, we have undertaken a long-term, double-blind, placebo-controlled study to assess the protective influence of baclofen on the course of HD. Since April 1982, 60 HD patients in stages I and II of illness have been evaluated and randomized to baclofen or placebo treatments. Subjects are re-evaluated at 6- to 12-month intervals in terms of clinical features (functional, motoric, cognitive, psychiatric, metabolic measures), radiographic correlates of caudate atrophy and chemical profile of the cerebrospinal fluid. Assessment procedures for HD are sufficiently sensitive to detect meaningful clinical changes within a 3-year period of observation. By early 1987, prospective evaluations will be completed in our entire cohort of HD patients, and analyses of major outcome variables will be undertaken. We anticipate that continuation of this project will result in: 1) a substantial body of knowledge regarding the natural history of HD in the early stages of illness, 2) therapeutically useful information for the care of HD patients and their families, and 3) a workable paradigm for the assessment of protective therapy in HD. If our hypothesis is confirmed, baclofen will represent the first substantive therapy for HD, by which future therapeutic strategies will be gauged.